DE2800480A1 - 4-SUBSTITUTED IMIDAZO ANGLE CLAMP ON 1.2 A ANGLE CLAMP ON -CHINOXALINE, INTERMEDIATE PRODUCTS, METHOD FOR THE PRODUCTION THEREOF AND MEANS CONTAINING THEM - Google Patents

Description

..atcntanWXlte 280 QA 8 0

PROF. DR. DR. J. REITSTÖTTER DR.-ING. WOLFRAM BUNTE DR. WERNER KlNZEBACH

BAUERSTRASSC 22, Ο-βΟΟΟ MUNICH 4O - FERNRUF (OSS) 37 OS 83 · TELEX MfSSO · ISAR D "* POSTAL ADDRESS: POST BOX 78Ο. D-BOOO MUNICH A *

Munich, January 5, 1978 M / 18 352

BRISTOL-MYERS COMPANY 345, Park Avenue, New York, N.Y. 10022 UNITED STATES.

4-Substituted imidazo [1,2-a] quinoxalines, intermediates, Process for their production and compositions containing them

809828/0896

M / 18 352

The invention relates to bestirainta 4-substituted imidazo- [1,2-a] quinoxalines and processes for their preparation. It also relates to certain 1- (2-acylaminophenyl) imidazoles which, among other things, are useful intermediates in the preparation of the 4-substitution. Imidazo C1, 2 ~ a] are quinoxaline. These compounds are useful for a variety of purposes, as will be further explained below, "Some have useful immunosuppressive properties, others are effective as anti-inflammatory agents or have anti-fungal effects." Some of these compounds also have two or all three effects.

The 4-substituted imidazo [1,2-a] -quinoxalines according to the invention these correspond to compounds of general formula I.

or the pharmaceutically acceptable salts thereof, in which:

8Q9828 / 0896

X is -R ¹ or -NHR ² , in which:

(1) R through a carbon-carbon bond to a Ring carbon atom is bonded and for an aliphatic, cycloaliphatic ^ substituted phenyl, fused bicyclic aryl or monocyclic aryl substituted aliphatic radical;

and 2

(2) R stands for a residue that has a carbon stick

substance bond is bonded to a nitrogen atom, i selects from · aliphatic, cycloaliphatic,; Phenyl, substituted phenyl, fused bicyclic Aryl radicals or aliphatic groups substituted by monocyclic aryl,

If R stands for an aliphatic group, this can be a straight-chain or branched, saturated, monounsaturated or polyunsaturated hydrocarbon group, R can also comprise a straight-chain or branched group which contains bonds other than carbon-carbon bonds, e.g. ether bonds, carbon-halogen bonds, etc. Generally it contains from about 1 to 18 carbon atoms, the most typical radicals in this group being alkyl radicals having from 1 to 18 carbon atoms.

In order to illustrate which aliphatic groups R can stand, the following are listed by way of example: CH ₃ -; CH ₃ CH ₂ -; CH ₃ CH ₂ -CH ₂ -; CH ₃ (CH ₂ J _n - , where η is 3, 4, 5, 6, 7, 8, 14 and 16, respectively; (CH ₃ I ₂ CH-CH ₂ -; CH ₃ (CH ₂ ) ₃ (CH ₃ CH ₂ ) CH ₂ = CH- (CH ₂ ) g-, alkoxyalkyl, where the alkyl radicals contain 1 to 4 carbon atoms, for example methoxymethyl; haloalkyl ( _{e.g. CH 2} Cl-; CH ₃ CHCl-; CHCl ₂ -; CCl ₃ - ; CH ₃ Br-; CF ₃ ) .

8Q9828 / D89S

2800430

M / 18 352 - 11 -.

If R stands for a cycloaliphatic radical, this is usually a cycloalkyl radical with 3 to 8 carbon atoms or a cycloalkenyl radical having 5 to 6 carbon atoms. Examples of cycloaliphatic radicals in formula I for R are:

Cyclopropyl (dhj;>); Cyclobutyl (dh \ y ) cyclohexyl *

Cyclohexenyl (ie ^ V ") and norbornenyl (ie J7

If R in the above formula I is a substituted phenyl radical, the phenyl group can have 1 to 5 substituents, but will generally be mono-, di- or trisubstituted. Typical examples of radicals that can be contained in the phenyl group are

(A) straight-chain or branched alkyl groups with 1 to 6 carbon atoms, for example methyl, ethyl, »tert-butyl;

(b) alkoxy groups having 1 to 6 carbon atoms, for example Methoxy, ethoxy;

(c) hydroxy groups;

(d) acyloxy groups with 1 to 18 carbon atoms,

(e) halogen, for example 1 or 2 Cl, F, Br or I atoms, preferably in the meta and / or para position;

(f) nitro groups;

(g) amino groups; ■ ·.

(h) Acylamino groups in which the acylamino radical is from an alkanecarboxylic acid is derived with 1 to 18 carbon atoms,

809828/0896

M / 18 352 '- 12 -

and benzamides, the benzene ring of which is unsubstituted, monosubstituted, disubstituted or trisubstituted can with alk groups, which 1 to 5 carbon atoms or contain halogen atoms?

(i) polyhydroxyalkylamino groups of 4 to 8 carbon atoms;

(j) cyano groups;

(k) trifluoromethyl groups,

(1) mercapto groups; (m) alkylthio groups;

(n) acylthio groups of 1 to 18 carbon atoms; (o) carboxyl groups;

(p) carbalkoxyl groups having 1 to 3 aliphatic carbon atoms ;

(q) phenyl radicals; (r) phenoxy radicals, and combinations thereof.

If R stands for a condensed bicyclic aryl radical, then this can be a substituted or unsubstituted radical, for example a condensed bicyclic hydrocarbon remainder like 1-naphthyl, 2-naphthyl, etc.

809828/0896

M / 18 352 - 13 -

R stands for one substituted by a monocyclic aryl aliphatic group, the monocyclic aryl moiety can either be substituted or unsubstituted. The aliphatic, The remainder of this group can either be a straight-chain or branched, saturated or unsaturated hydrocarbon residue be or can also be .other than carbon-carbon bonds contain. Examples include groups such as phenoxymethyl; Benzyl, styryl,

2 2

The group R in the radical -NHR of the above formula I can have the same meanings as given above for -R. In addition, R can also stand for phenyl, such as

in the group -

In general, the above compounds of the formula I as well as those compounds of the formula I in which X is Hydrogen or phenyl can be prepared by adding the corresponding 1- (2-acylamidophenyl) imidazole Reflux temperature with a cyclizing agent, for example polyphosphoric acid or phosphorus oxychloride, etc. in cyclized in sufficient amount until a significant cyclization is achieved.

809828/0896

M / 18 352

The 1- (2-acylaminophenyl) imidazoles used in this procedure can be used, correspond to the general formula II:

wherein X ^{2 is} R ⁵ or -NHR ² , wherein:

R represents hydrogen or an aliphatic, cycloaliphatic phenyl or substituted phenyl, condensed bicyclic Aryl radical, or aliphatic groups substituted by monocyclic aryl.

R has the same meanings as are listed above in connection with formula I.

The group R in formula II has the same meanings as given for R in formula I, moreover, can However, R also stands for the phenyl radical. The reaction can be represented by the following equation:

Phosphorus oxychloride

Reflux

III

809828/089 $

M / 18 352 - 15 -

The process of Equation III is preferably carried out in the presence of an excess of an organic amine solvent carried out. A variety of solvents can be used for this purpose, such as pyridine, 2,6-dimethylpyridine, Ν, Ν-diinethylaniline, trimethylamine, N-methylmorpholine, ect. Preferred organic solvent however, is pyridine. · ■ ■

The amount of phosphorus oxychloride used in this reaction can fluctuate a little. In general, however, the range of phosphorus oxychloride used is about 1/2 mole to about 6 moles / and preferably from 1/2 mole to 2 moles per mole of compound II.

The desired product of the formula IV can be obtained from the reaction mixture by the customary methods known to the person skilled in the art be won. The reaction time depends, among other things, on the particular reactants used and the molar ones Quantities of the reagents. In general, the reaction time is about 30 to 120 minutes.

The temperature used in carrying out the process is also dependent on the particular reagents chosen, the solvent and other factors. In general carried out at reflux temperature of the reaction mixture, which is generally in a range of about 95 ⁰ C to 195 ⁰ C. ■ · ■ · · ■

The process for the preparation of the 1- (2-acylaminophenyl) -imidazoles (Compound II) also varies depending on the particular type of compounds to be made. If you ask for example compounds of the general type V:

809828 / Q896

M / 18 352

. O ¹¹ 5

NHCR

wherein R is hydrogen, aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic Aryl radicals or aliphatic groups substituted by monocyclic aryl is 1- (2-acylaminophenyl) imidazole with the appropriate acid halide, for example the acid chloride, reacted.

This can be represented by the following equation:

VI

Il

NHC-R

wherein R has the meanings given above.

the reaction is usually carried out using equimolar amounts of the appropriate acid chloride and in the presence of an excess of solvent. (e.g. pyridine) at reflux temperature through.

809828 / D896

M / 18 352

When it comes to compounds of the phenylureylene type, for example of the formula

where R is hydrogen, aliphatic cycloaliphatic, Phenyl, substituted phenyl, fused bicyclic aryl radicals or substituted by monocyclic aryl If there are aliphatic groups, the aminophenylimidazole is used with the appropriate isocyanate.

This can be represented with the following equation:

VIII

R ² NCO

NH,

NH-C-NHR ²

wherein R has the meanings given above; These The reaction is preferably carried out in the presence of a solvent and at steam bath temperature. A typical solution agent that can be used is toluene and the reaction participants are generally used in equimolar amounts. The products obtained in reactions VI and VIII can be prepared by standard methods known to those skilled in the art

809828/0896

Preparation of 1- (2-acylaminopheny1) imidazoles

The 1- (2-acylaminophenyl) imidazoles of the invention are prepared according to the general methods described above. Tables I to IV below indicate the specific process that was used in the preparation of the respective compounds and also include the physicochemical properties of the compounds obtained. Melting points were measured by the capillary tube method using a Mel-Temp melting point apparatus and are uncorrected. ultraviolet spectra were measured in ethanol solution using a Beckman UV Acta III or a Beckman DBG device. 1- (2-aminophenyl) imidazole was made as described by AF Pozharskii, AM Siminov and LM Sitkina, KhIm. Geterotskl. Soedin., 5 , 1916 (1969). [Chem. Abstr., Τ2 ^, 11427 ^a (1970)].

Table I below shows the preparation of the .invention Amidophenylimidazoles with aliphatic, cycloaliphatic and are substituted by aliphatic radicals substituted by monocyclic aryl.

Table II shows the preparation of the aryl amidophenyl imidazoles • the present invention, including the condensed Ary! Compounds.

809828/0896

Unless otherwise indicated in Tables I and II, the amides are prepared by adding equimolar amounts of the appropriate acid chloride with 1- (2-aminophenyl) imidazole in the presence of an excess of pyridine for 45 minutes implemented over a steam bath. The reaction mixture is then stirred in ice water and the crude product is stirred accordingly one of the following methods.

Method A

If a solid is obtained, it is crystallized directly from the solvent given in Table I.

Procedure B

When you get an oil, you dissolve it in a minimal amount ^; Chloroform and sends it through a column of alumina, which is about twenty times the weight of the crude solid, and elutes with chloroform. The chloroform is then evaporated and the crude product is crystallized as indicated in Table I.

Procedure C

If a solution is obtained in the ice water mixture, the pyridine / water azeotrope is removed until the crude product is deposited. It is then processed further as described in method B.

809828/0896

TABEL

+ RC-Cl

CD CD 00 KJ

O OO CO

■ No.

1- (2-alkanamidophenyl) imidazoles

Isolation% Crystallization

process yield solvent mp. ⁰ C

63.3

water

CH ₃ -

56.2 ethanol

73.9 water

CH ₃ (CH ₂ ) 2 "CH ₃ (CH ₂ ) ₃ -

31.1

toluene

49.6 toluene / hexane

200-204

163-166

144-146

108-110

123-125

Analysis%
calculated found

C 64.16 H 4.85 N 22.45

C 65.66 H 5.51 N 20.88

C 66.96 H 6.09 N 19.52

C 68.10 H 6.59 N 18.33

C 69.11 H 7.04

64.26

4.71

22.30

65.69

5.52

20.84

67.26

6.15

19.40

67.95

6.52

18.25

69.14 7.00 17.17-

CH ₃ (CH ₂ ) ₄ -CH ₃ (CH ₂ ) ₅ -

CH ₃ (CH ₂ ) ₆ -

CH ₃ (CH ₂ ) ₇ -CH ₃ (CH ₂ ) ₈ -CH ₃ (CH ₂ )

12 CH ₃ (CH ₂ )

14 (CH ₃ ) ₂ CHCH ₂ -

Isolation
procedure yield Crystallization
solvent Mp ° C analysis
calculated 70.01
7.44
16.33 found M / 18 OO
CD
CD B. 49.4 Isopropyl ether
Trichlorethylene 103-105 C.
H
N 70.82
7.80
15.48 70.31
7.45
16.26 ω
Ul
to OO
CD A. 55.3 Isopropyl ether 96-98 C.
H
N 71.55
8.12
14.72 70.7 9
7.74
15.23 A. 55.1 Isopropyl ether 101-102 .C
H
N 72.21
8.42
14.03 71.67
8.05
14.65 A. 45.6 Isopropyl ether 93-95 C.
H
■ N 72.81
8.68
13.41 72.24
8.41
13.92 A. 60.6 Isopropyl ether
Hexane 79-81 C.
H
N 75.52
9.89
10.57 73.38
8.85
13.02 I.
to
-j. B. 58.1 Isopropyl ether 94-96 C.
H
N 76.19
10.18
9.87 75.12
9.76
10.38 I. B. 80.6 Isopropyl ether 98-100 C.
H
N 69.11
7.04
17.27 76.57
10.28
9.79 C. 48.8 benzene 102-104 C.
H
N 69.40
6.66
17.34 69.15
7.26
17.19 C. 25.4 benzene 128-130 C.
H
N 69.60
7.00
17.40 I.

No.

Isolation% crystallization process Yield solvent

j 15 CH ₃ (CH ₂ ) 3 (CH ₃ CH ₂ ) CH- B

; 16 CH ₂ -CH- (CH ₂ ) ₈ -

σ j 19 'CH-CH ₉ (^ O) CH-C

-CH = CH-

CH ₃ OCH ₂

32.8

76.8

j 17 CH ₃ (CH ₂ ) ₃ (CH ₂ -CH = CH) ₂ (CH ₂ J ₇ -C 3.6

41.9

7.7 43.0 49.8 77.7

benzene

Ethanol

toluene

Toluene mp ° C

125-127

Isopropyl ether
Hexane 92-94 C. 73.76 Ethanol 145-147 Diethyl ether 205-207

161-164

146-147

Analysis% calculated found

C 71.55
H 8.12
N 14.72

C 73.81
H 8.36
N 12.91

C 76.92
H 9.32
N 9.97

C 73.63
H 5.45
N 15.15

C 74.73
H 6.27
N 13.76

C 74.72
H 5.23
N 14.52

C 62.33
H 5.66
N 18.17

71.86

7.84

14.95

74.26 ·

8.50

12.30

76.73 9.36 9.78

73.81

5.57

15.41

74.83

6.32

13.59

74.94

5.47

14.55

61.99

5.74

18.48

136 5- C. 69 , 61 69 , 82 138 5 H 5 , 15 5 , 37 N 14th , 33 14th , 04

Ca) Ul N)

No. 23

! 24.

co I

25 26

Isolation% Crystallization Process Yield Solvent

O-

10.1. Isopropanol

55.6 toluene

67.3

21.6 11.9

toluene

Ethanol

water

Mp ° C calculated 207-209 C 68.71 H 5.76 N 18.49 151-153 ~ C 69.69 H 6.27 N 17.41 142.5- C 71.35 145 H 7.11 N 15.60 196-198.5 C 72.16 H 6.06 N 15.78 255 (decomp.) C 56.06 H 4.28

Analysis%

found

N 17.83

68.67

5.85

18.67

69.44

6.21

17.55

70.88

6.92

15.59

71.87 6.33

15.40

55.92 4.26

17.72

28 1 29 1
i CH ₃ CICl- A. . 27.9 toluene 143.5- C 57.72 57.54 ro 145.5 H 4.85 4.92 co ι N 16.83 17.16 Q A. 33.2 Benzene " 162-165 C 48.91 48.94 O H 3.36 3.24 CO N 15.56 . 15.42 O • Cl 26.25 . 26.17 ■

00 NJ OO

No. R. CP ₃ -.
O Isolation% Crystallization
process yield solvent · mp. ⁰ C analysis
calculated found • M / 18 ■ 1 I. 2800480 30th CH ₃ CH ₂ OC- A 22.0 ethanol * 165-167 C 51.77
H 3.16
N 16.47 51.58
3.20
16.53 352 ro
l • 32 Notes: ^ C. 14.1 trichlorethylene 128-130 C 60/23
H 5.05
N 16.21 60.21
5.10
16.16 a) • Could not be crystallized; was chromatographed on miminium oxide with ethyl acetate as the eluent
cleaned. Prepared from acetic acid-formic acid anhydride according to R. J. Jones, J. Am. Chem. Soc. , 71, 644 (1949) b) After distilling off
NaOH neutralized, of the excess solvent, the residue is dissolved in water and with
thereby obtaining the crude product. • c) Manufactured via the anhydride.

Tabel

No.

34

35

36

Ar

CH.

CH.

+ Ar-O-Cl

1- (2-arylaidopheny 1) -imidazoles

Insulation%

process yield crystallization

Solvent Pp. C

Λ max. (Am)

44.9 dimethoxyethane 148-150 225 (21,720)

58.7

58.3

57.4

Ethanol

benzene

Benzene 190-192.5 262 (21 400)

147-148.5 231, sh (18.20Q)

143-146.5 236 (23 400)

Calculate analysis% found ι

C 72.99
H 4.98
N 15.96

C 73.63
H 5.45
N 15.15

C 73.63
H 5.45
N 15.15

73.30

5.08

16.04

73.10

5.32

15.46

73.63

5.24

15.36

C. 73 , 63 73 , 28 H 5 , 45 5 , 29 N 15th , 15 15th , 27

No.

38

39

42

43

Ar

CF

NO--

Isolation% Crystallization Process Yield solvent. M.p. ⁰ C Amax. (At the)

53.0 benzene

79.3 ethyl acetate

45.5 isopropanol 151-153

56.8 benzene 205-208

c.

136-138 '239 (20,400)

198-200 276 (28 100)

73.5 dimethylformamide 194-196 260 (17 810)
Methanol

74.4 dimethylformamide 198-202.5 250 (16,500)
water

A 87.41 dimethylformamide 254-256 c. water

A 60.87 dimethylformamide 219-220.5 234 (1,500) water

229 (18 500)

Analysis% ^ calculated found °°

LO

60.97 3.62 12.34

75.06 6.45 13.31

77.46 4.76 12.09

62.26 ι 3.69 to 18.10 ^Λ

62.27 4.00 18.37

C 61.63 H 3.65 N 12.68

C 75.21 H 6.63 N 13.27

C 77.86 H 5.05 N 12.38

C 62.33 H 3.92 N 18.17

C 62.33 H 3.92 N 18.17

C 54.40 H 3.14 N 19.82

54.35

3.31

19.82

C. 70.82 70.14 I. OO H 4.20 4.45 CD N 19.49 19.15 CD 4> - C. 68.32 67.86 CO H 4.30 4.02 O N 14.94 15.17

OO NJ OO

co co or »

No.

47 48

Ar

Br

Cl

Cl

Isolation% Crystallization

process yield solvent. Fp. C Λ max. (Am)

A 53.2 ^a dimethylformamide 93-96 260 (10 100) water

b) dimethylformamide 189-190.5 "240 (22 100)

A 40.1 dimethylformamide, 199-201.5 258 (20 100) water

A 38.7 pimethylformamide, 201-203 261 (16,700) ethanol

B. 68.5 ethanol

59.7 ethanol 144-146

c)

167-170 240 (26 410)

26.6 dimethylformamide, 210-212 265 (21,000)
water

61.2 dimethylformamide, 180.5-183 235 (22 100)
water

Analysis% ^ s

calculated found co

C 66.20 65.96 H 4.51 4.37

N 14.47 14.40

C 56.16
H 3.53
N 12.28

C 56.16
H 3.54
N 12.28

C 64.54
H 4.06
N 14.11

C 64.54
H 4.06
N 14.11

C 64.54
H 4.06
N 14.11

C 57.85
H 3.34
N 12.65

56.03

3.58

12.51

55.84

3.58

12.48

64.70 4.05 ι 13.95 ν »

64.82 '3.92 14.59

64.41

3.94

13.92

58.05

3.46

13.08

C. 57, 85 57 , 65 H 3, 34 3 , 51 N 12, 65 12th , 93

OO O O

O (O OO

co co cm

No.

54

55

56

57

58

59

Ar

OCH-,

Isolation crystallization

process yield solvent. it>. ⁰ C \ max. (Am)

OCH-

Br

42.9 ethanol

B 58.6 isopropanol

146-151

61.2 benzene 186.5-189 255 (28 480)

263 (20 400)

B 83.2 dimethylformamide 171-173 281 (5 100)

Water 130-132.5 244, sh (12300)

29.79 dimethylformamide, 133.5-136.5 281 (15 410)
water

18.26 dimethylformamide, 164.5-166.5 c)
water

51.07 isopropanol 142.5-145.5 223 (14 420)

Analysis% S

calculated found »

C 49.38 H 3.11 N 10.80 J 32.61

C 69.61 H 5.15 N 14.33

C 69.61 H 5.15 N 14.33

C 66.86 H 5.30 N 13.00

C 69.61 H 5.15 N 14.33

C 56.16 H 3.54 N 12.28

C 68.32 H 4.30 N 14.94

67.79

4.36

14.58

49.22

3.15

10.85

32.89

69.01

5.14

14.36

69.27

5.02

14.28

66.97 ^s 5.08 '13.54

69.10 5.08 14.18

55.65

3.51

12.37

CJO CD CD 00 KJ CX)

No.

190.

217

Ar

Isolation% Crystallization Process Yield solvent

Mp. ⁰ C

λ max. (Am)

15.68 'isopropanol-ethanol

46.9

Isopropanol 203.5-205 258 (18 840)

165.5-167.5 237 (53,900)

36.78 isopropanol 175-177 289 (6,940)

Dimethylformamide

38.80 benzene

45.8 ethanol 156-157.5 268 (13 800)

134-136.5 273 (14,900)

Analysis calculated

% found

C 54.40 H 2.28 N 11.90

C 76.66 H 4.83 N 13.41

C 76.66 H 4.82 N 13.41

C 64.58 H 5.42 N 11.89

C 66.86 H 5.30 N 13.00

Note: a) Isolated in the form of the hemihydrate.

b) Partial loss made it impossible to determine the yield.

c) The compound had too low absorption values to give a meaningful UV spectrum.

53.78

2.30

12.16

76.29

4.84

13.27

76.68

4.75

12.01

64.58

5.39

12.09

66.88

5.37

12.68

M / 18 352 - 30 -.

The alkyl-2- (1-imidazolyl) -phenylureylenes listed in Table III are prepared by adding equimolar amounts of aminophenylimidazole and the appropriate isocyanate in toluene at steam bath temperature for 2 or 3 hours. After cooling, the crude product is collected by filtration and one of the following methods treated:

(A) Direct crystallization from the appropriate solvent, or

(B) Dissolve in hot dimethylformamide, precipitate with water and then crystallize.

809828/0896

at oo co o>

CH ₃ -

Table III

N 0

.NHC-NHR

Alkyl 2- (1-imidazolyl) phenylurylenes

Isolation% Crystallization

method yield solvent m.p. C

. A max. (Am)

41,6 - ethanol 194-196 '240 (15500)

Analysis% calculated found

C 61.60
H 5.59
N 25.91

61.22

5.48

26.11

65 CH ₃ CH ₂ - B. 27 , 3 . Trichlorethylene 173-175. 278 (1
242 (12 200)
700) C 62.59
H 6.13
N 24.33 62.21
6.04
24.32 ro
OO 66 B. 49 , 3 Trichlorethylene 139-141 279 (1
240 (12 200)
800) C 63.92
H 6.60
N 22.93 63.75
6.56
23.00 CD
CD 00
O

Isolation% Crystallization Process Yield Solvent, Analysis%
>. ⁰ C / (max. (A m) calculated found

67 CH ₃ CH ₂ CH ₂ CH ₂ -

35.6 isopropanol 115-116.5 278 (1,400)
241 (15,000)

50.64 dimethylformamide- 164-166 241 (12 200)

water

00 σ to oc

Q 65.09
H 7.02
N 21.69

C 67.58
H 7.09
N 19.70

64.84

7.00

21.78

'67, 60

7.08

19.44

The aryl-2- (1-imidazolyl) -phenyl-ureylenes listed in Table IV are prepared by adding equimolar amounts
of the aminophenylimidazole and the appropriate aryl isocyanate in dry toluene for 3 hours at steam bath temperature. The reaction mixture is then cooled and the crude product is collected by filtration, washed with ether and crystallized from the specified solvent.

809828/0896

Table IV

OJ Ul N)

OO CD CD OO NJ OO * ■>. O OO CO CD

No.

Ar

CH-

+ ArNCO

NHCNHAr

Aryl-2- (1-xmidazolyl) -phenylureylenes

% Crystallization

booty solvent m.p. C. Amax. (At the)

64.6 ethanol

201-203 256 (27 640)

76.9 dimethylformamide 203.5-207.5 258 (23 400)
water

76.9 ethanol 182-183.5 256 (25 800)

78.8 dimethylformamide- 202.5-203.5 251 (25 500)

water

Analysis% calculated found

C 69.05 H 5.07 N 20.13

C 69.84 H 5.52 N 19.17

C 69.84 H 5.52 N 19.17

C 64.86 H 4.42 N 18.91

69.13 5.15 20.16

69.85 5.47 19.28

69.97

5.35! So 19.12 CO CD

64.77 CD 4.47 <£ - 19.16 OO CD

Ar

κ>
cxi

Br

Br

% Off oncrystallization

booty solvent m.p. C

max. (Am)

Analysis% calculated found

61.9 dimethylformamide 201-202 253 (26,000) water

65.8 dimethylformamide 220-222 251 (23 100) water

76.7 dimethylformamide 204-206 258 (30,900) water

58.1 dimethylformamide 244-245.5 260 (32,900) water

70.0 dimethylformamide 180.5-182.5 252 (23,000) water

75.2 dimethylformamide 218-219.5 258 (28,600) water

53.1. Methanol

227-230.5 .260 (27 700)

83.2 dimethylformamide 201-202 253 (26,000) water

C 64.86
H 4.42
N 18.97

C 64.86
H 4.42
N 18.97

C 61.45
Η '4.19
N 17.91

C 55.35
H 3.48
N 16.14

C 53.80
H 3.76
N 15.68

C 53.80
H 3.67
N 15.68

C 53.80
H 3.67
N 15.68

64.47

4.40

19.24

64.56

4.41

19.14

61.57

4.12

18.26

54.93

3.47

16.25

53.88

3.78

15.66

53.71

3.66

15.35

52.08

3.56

15.12

C. 64 , 86 64 , 47 H 4th , 42 4th , 40 N 18th , 97 19th , 24

No.

Ar

% From recrystallization yield solvent mp. ⁰ C ) \ max. (Am)

Analysis% «

calculated found S

CH ₃

CF.,

57.79 dimethylformamide water

77.4 dimethylformamide water

78.9 dimethylformamide water

76.6 dimethylformamide water

76.2 dimethylformamide water

67.8 dimethylformamide water

80.6 dimethylformamide water

69.0 dimethylformamide water

167-170 250 (20 710)

216.5-218.5 256 (31 010)

212-215-260 (27 580)

185-188 258 (29 590)

163.5-166 258 (20 770)

169-172 257 (29 920)

206-209

(27 620)

204.5-206 285 (10 630)

C 69.84

H 5.52

• N-19.17

C 58.96
H 3.78
N 16.18

C 70.57
H 5.92
N 18.29

C 70.57
H 5.92
N 18.29

C 70.57
H 5.92
N 18.29

C 71.83
H 6.63
N 16.75

C 71.23
H 6.29
N 17.49

70.10

5.57

18.60

58.86

3.81

15.79

70.30

5.83

18.00

70.30

5.96

18.00

70.52

5.81

17.94

71.61

6.56

16.24

71.12

6.12

17.24

C. 66 22nd 65, 96 H 5, 23 5, 15th N 18 17th 18 15th

Ar

% The end
prey tiricrystallization
solvent Ep. ⁰ C X max. (25 (At the) Analysis%
calculated found 66.22
5.23
18.17 65.83
5.13
18.02 § (24 66.22
5.23
18.17 65.61
5.14
17.98 CO 84.0 Dimethylformatnide
water 188 252 (27 510) C.
H
N 67.07
5.63
17.38 66.80
5.62
17.36. U)
Ui
to 81.9 Dimethylfontiamide
water 200-202 260 (26 560) C.
H
N 68.55
6.33
15.99 68.68
6.34
15.62 80.9 Dimethylformamide
water '190.5-193 259 (35 180) C.
H
N 71.34
4.90
15.13 71.14
4.93
14.78 79.5 Dimethylfontiamide
water 178-179.5 258 (32 490) C.
H
N 62.94
4.97
17.27 62.84
4.86
17.22 ι I 64.1 Diethylformaldehyde
water 202.5-205 259 (30 850) C.
H
N 61.45
4.19
17.91 60.94
4.02
17.79 I. 75.1 Dimethylformamide
water 189-191 278 (25 130) C.
H
N 61.44
3.85
17.83 61.33
3.92
17.98 j 62.3 Dimethylformamide
water 211.5-214.5 259 210) C.
H
N I. 75.9 Dimethylformamide
water 198-210 252 230) C.
H
N OO
CD i
<=>! OO
CD

No.
97

98
99
100

101
102
103
104

Ar

% Yield

64.8

70.7

70.0

57.6

50.7

42.7

44.2

52.3 Recrystallization Solvent

ip. ⁰ C

max. (Am)

Analysis% calculated found

Dimethylformamide 232.5-234 258 (32,380)
water

Dimethylformamide water

Dimethylformamide water

237.5-239 258 (31,300)

229-232

(25 630)

Dimethyrformamide 239.5-242.2 261 (37 430)
water

Dimethylformamide 190-192 255 (26 350)
water

Dimethylformamide- 202-205 375 (4,200)
Water 253 (32 970)

Dimethylformamide water

Dimethylformamide water

237.5-239.5 342 (1,800)
(46 530)

> 257 (decomp.) 330 (20 010)

C 55.35 H 3.48 N 16.14

C 62.48 H 4.63 N 17.15

C 58.10 H 3.66 N 16.94

C 53.63 H 3.18 N 14.71

C 53.63 H 3.18 N 14.71

C 59.44 H 4.05 N 21.66

C 59.44 H 4.05 N 21.66

C 59.44 H 4.05 N 21.66

55.60

3.50

16.00

62.79

4.70

17.30

"57.84

3.56

16.90

53.89

3.05

14.41

53.70

2.97

14.90

59.40

4.10

21.44

59.16

4.10

21.31

59.01

3.97

21.07

Ar

tIO "

% Of crystallization

booty solvent ip. C.

max. (Am)

35.4 dimethylformamide-256.5-258 257 (33,080) water

57.1 dimethylformamide 254-256 x 256 (36,930) Water., (Decomp.)

47.3 pimethylformamide water

(57 510)

33.8 dimethylformamide 227.5-229.5 297 (32,710) water ■

35.2 dimethylformamide 233-236. 284 (16,710) water

25.2 dimethylformamide-231-232 252 (32,920) methanol-water

Analysis% calculated found

C 53.72
H 3.38
N 19.57

C 60.53
H 4.48
N 20.76

C 67.32
H 4.32
N 23.09

C 67.48
H 5.03
N 17.49

C 73.15
H 4.91
N 17.06

53.72

3.31

19.63

60.26

4.34

20.68

67.88

4.13

21.37

67.49

5.05

17.07

72.70

4.97

16.63

C 56.31 54.13 H 3.55. 3.50 N 20.52 20.21

M / 18 352

Preparation of 4-substituted imidazo [1-, 2-a] -quinoxalines

The 4-substituted imidazo- [1,2-a] -quinoxalines according to the invention are prepared according to the procedures described above for the corresponding 1- (2-acylaminophenyl) imidazoles. Tables V through VIII below show that used in the preparation of each particular compound Process, as well as the physico-chemical properties of the compounds obtained.

4-Alkylimidazo [1,2-a] -quinoxalines (Table V) are prepared by mixing the appropriate amide (Table I, Compounds 1 to 33) with phosphorus oxychloride in an excess of pyridine heated to reflux for 1 hour. The reaction mixture is then stirred in ice water and so much azeotrope is removed until a viscous residue forms, which is dissolved in chloroform, over MgSO. dried and on an aluminum oxide column is chromatographed. Then the chloroform is evaporated and the product crystallized from the specified Solvent.

809828/0898

Table V

CD CXJ NJ OO

109 H-

112 CH ₃ CH ₂ CH ₂ -

113 CH ₃ (CH ₂ ) ₃ -

+ Phosphorus oxychloride

4-alkyl imidazo [1,2-a] quinoxalines

% Of recrystallization

booty solvent m.p. C

63.3. Sublimated

13.3. Isopropyl ether

37.6 hexane

14.3 hexane

17.6 hexane

114-115

110-111

92-93

. (At the)

(10 900)

(11 200)

"311 (10 500)

(10 900)

(8,000)

ω cn to

Analysis%
calculated found

C 72.11
H 4.95
N 22.93

C 73.07
H 5.62
N 21.30

72.18

4.89

23.01

72.85

5.83

.21.29

C. 73 , 91 73 , 99 H 6th , 20 6th , 13 N 19th , 89 19th , 94

C 74.64
H 6.70
8th

74.34
6.74
1, -48-

CD CD JS OO O

co Ό co

co co a *

No.

114

% From recrystallization yield solvent

Pp. ° C

CH ₃ (CH ₂ ) ₄ -

115 CH ₃ (CH ₂ ) ₅ -

116 .CH ₃ (CH ₂ )

117 CH ₃ (CH ₂ ) ₇ -

118 CE, (CH ₀ ) _B

119 CH ₃ (CH ₂ )

120 CH ₃ (CH ₂ )

29.2 b)

10.7 b)

8.0 c)

26.3 isopropyl ether

9.5 ethyl ether-hexane

24/3. Isopropyl ether

13.7 isopropyl ether

63-65

43-45

54-57

65-66

55-57

73-75

79-81

} \ max. (Am)

(11 300)

(10 800)

(9 400)

(11 600)

(12 500)

(11 300)

(11 300)

Analysis% bereclinet found

C 75.28
H 7.16
N 17.56

C 76.83
H 8.24
N 14.93

C 77.25
H 8.53
N 14.22

C 79.11
H 10.14
N 10.31

75.13

7.39

17.43

C 75.86 76.03

H 7.56 7.63

N 16.59 16.40

C 76.37 "75.84

H 7.92 7.77

N 15.72 16.43

76.97

8.20

14.89

77.04

8.36

14.52

C 79.11 79.03 H 9.82 10.02 N 11.07 10.88

79.54 10.12 10.34

u> ui to

I.
! IZI (LHa / rtLrLiiA I ^ / 6th Hexanes 52-55 314 (11 700) C.
H
N 74
6th
18th , 64
, 71
, 65 74
6th
18th , 92
, 81
, 74 CO
CD
O 1st floor
CZ

No.

122

OO NJ OO

α co co

125

126

127

128

CF ₃ -

123 . CH ₂ = CH (CH ₂ ),

124

CH ₃ CCH ₂ -

O-

% Training Itnkristallisations-

booty solvent m.p. ⁰ C λ max. (Am)

Analysis% κ calculated found ^ T

50.7 ispropyl ether-chloroform

9.8 hexanes

16.7 % ethanol

14.5 ethanol

37.2 x benzene

17,9 'hexane

9 140.5-142 328 (10 800) (11 500) C. 55.70 55.94 CJ 184-187 H 2.55. 2.49 cn N 17.72 17.64 96.5-97.5 309 (13 100) C. 78.14 77.92 40-42 H B-, 20 7.98 N 13.67 13.96 146.5-148.5 312 (13 100) C. 78.74 78.59 H 5.05 5.20 N Ί6.20 16.10, 164-167 312 (10 600) C. 67.59 67.04 H 5> 20 5.17 N 19.71 19.93 106.5-107.5 314 (10 400) • c 74.17 74.20 I. H 4.76 4.61 CO N 15.26 15.09 I. 286 (10 500) C. 79.68 80.38 H 4.83 4.91 N 15.49 15.12 310 C. 75.31 75.32 H 5.87 .5.84 N 18.82 18.75 K) OO O ₍ O OO O

i% from non-crystallization analysis% _a

^! No. R booty solvent m.p. ⁰ C λ ¹¹⁰ X- (Am) calculated found ^

129 <> - 2.0 hexane 119-120.5 311 (11,400) C 76.46 £ 76.65

CD
IO
OO

C 76 , 46 76 65 H 6 , 82 6, 76 N-16 , 72 16, 58

130 O ^- ° ^'8 isopropyl ether 133-135 312 (11 700) C 77.20 7.7,39

^ - ^ H 5.68 6.13

N 16.92 16.76

Notes: a) AM Siminov and IG ürykina, Khim. Geterot. Soedin ., T_> 570 (1971) describe for this

Compound a m.p. 124 ⁰ C at ^ ** ²⁰⁰ (Am) = 315 (10700)).

c) Purified by distillation at 174-184 ° / 0.40 rtm pressure.

b) Purified by sublimation at 90 ° / 0.15 mm pressure. '*>.

The 4-arylimidazo [1/2-a] -quinoxalines listed in Table VI are, unless otherwise stated in the table, prepared according to the general procedure, such as it is described for the 4-alkylimidazo [1,2-a] quinoxalines.

809828 / D898

Table VI

oo σ co oo ro oo

co cn ro

Ar

NHC-Ar + phosphorus oxychloride

4-Aryl- · imidazo [1,2-a] -quinoxalines

% Yield from crystallization solvent, melting point ⁰ ° C

X max. (Am).

Analysis% calculated found ι

CH-

CH-

34.8 benzene

37.2 toluene

Isopropanol

35.9 isopropanol

Isopropyl ether

47.1 isopropanol

145-147

(14 100) '

149-150.5 334 (22 650)

112-114

119-120 (15 400)

(18 100)

C 78.35 H 4.52 N 17.13

C 78.74 H 5.05 N 16.20

C 78.74 H 5.05 N 16.20

78.70

4.38

16.90

78.89

5.08

16.27

78.53

5.19

16.20

CO j O! CD

C. 78 , 74 78 32 j>. H 5 , 05 4, 73 OO N 16 , 20 15, 93 'O

No.

135 136

Ar

% Yield

37.8

47.0

Recrystallization Solvent M.p. C

Isopropanol

Isooctane 136-137

112-113

max. (Am)

(27 780)

(10 411)

Analysis% calculated found

C 82.22

Ή 4.70

N 13.07

C 65.18 H 3.22 N 13.41

82.06

4.38

12.89

65.03

3/10

13.62

(CH ₃ ) ₃ C -O

138

139

CH ₃ O

CH ₃ O

56.7 hexanes

37.2 isopropanol-toluene

51.5 isopropanol 105-107

(20 354)

149-150.5 334 (22 650)

136-138 329 (16 600)

C 79.70 H 6.35 N 13.94

C 74.17 H 4.76 N 15.26

C 70.81 H 4.95 N 13.76

79.59

6.58

13.84

74.18

4.79

15.33

70.61

5.06

13.56

140 141 142

31.5 ethanol

6.8 benzene hexanes

35.2 isopropanol 173-175

166-168

133-134

(16 280)

(10 300)

(14,000)

C 68.70 H 3.60 N 15.02

C 68.70 H 3.60 N 15.02

C 68.70 H 3.60 N 15.02

69.06

3.28

15.08

68.77

3.48

14.87

68.43

3.45

14.89

1st floor N3 OO

Ar

Cf

NO ₂

% The end
prey crystallization
solvent Mp ° C •
X max. (16 (At the) Analysis%
calculated found 61.16
.2.89
13.37 60.94
2.82
13.50 M / 18 61.9 toluene 215-217.5 333 (13 530 C.
H
N 61.17
2.89
13.37 60.61
2.85
13.57 LO
Oil
to 3.4 Carbon tetrachloride 168-170 321 (10 030) C.
H
N 59.28
3.11
12.96 58.75
3.03
12.90 24.1 Dimethylformamide
water 161.5-164.5 319 (12 200) C.
H
N 59.28
3.11
12.96 59.34
3.13
13.23 13.4 Dimethylformamide
water 172 329 (14 900) C.
H
N 72.99
3.83
15.96 73.00
4.06
15.77 I.
00
I. 39.1 Isopropanol 183-185 328 (48 500) C.
H
N 70.58
3.83
14.52 70.54
3.71
14.67 15.0 . Ethanol 190-192 222 (14 000) C.
H
N 75.54
3.73
20.73 75.15
3.85
20.66 53.3 Dimethylformamide
Water" 257.5-259.5 335 (13 900) C.
H
N 66.20
3.47
19.30 66.10
3.48
19.53 K)
OO
CD 59.8 2-ethoxyethanol 220.5-222.5 333 850) C.
H
N CD
OO
O

No.

151

152

153

154

Ar

NO ₂

NO,

C.

CH ₃ CNH

1/3

V-> J

= r \ 11 H / = \ ^d

156

173

157

% Yield

40.3

52.5

75.7

61.9

58.0

· 1/3 H ₂ O 13.9

32.3

56.6 Recrystallization Solvent

Mp ° C

Analysis%
max. (Am) calculated found ^.

toluene 249-252 346 (15 269) C.
H
. N 66.20
3.47
19.30 66.10
3.44
19.28 Dimethylformamide 283-285 340 (10 880) C.
H
N 57.30
2.71
20.89 57.08
2.74
21.11 Dimethylformamide
water
Dimethylformamide
water 198-199.5
130-133 • 369
326 (23
(14 470)
830) C.
H
N
C.
H
N 73.83
4.65
21.53
73.83
4.65
21.53 73.48
4.69.
.21.54
73.56
4.78
21.69 Ethyl acetate-hexane 214-217 342 (27 700) C.
H
N 68.88
4.66
17.85 68.46
4.99
17.76 Dimethylformamide
water 237.5-240 345 (32 350) C.
H
N 68.24
3.90
13.84 68.54
3.90
14.00 Ethanol 155-157 321 (13 090) C. 72.99 72.44

Dimethylformamide water

134.5-136 332 (14 260)

Br

H 3.83
N 15.96

C 59.28
H 3.11
N 12.96

3.83
16.14

59.25

3.04

13.11

CD CD • ΓΟΟ CD

co co ro co

No.

158

159

160

161

162

163

164 CH ₃ (CH ₂ )

Ar

165 CH ₃ (CH ₂ ) £ Ο-ά

% Yield from uncrystallization solvent

47.5 dimethylformainide water

52.7 ethanol

10.62 chloroform

43.2 benzene

25.4 isopropanol

84.2 ethanol

80.3 ethanol

62.6 ethanol m.p. ° C

max. (Am)

Analysis% »

calculated found S approx

132.5-134 330 (13,970)

113-114.5 329 (16,500)

159-161.5 323 (15 290)

154.5-156.5 340 (21,800)

210-215 343 (23 800)

158-160 333 (14 950)

116-118 335 (15 100)

90.5-93.5 335 (15 100)

C 72.99 H 3.83 N 15.96

C 74.17 H 4.76 N 15.26

C 81.34 H 4.43 N 14.23

C 81.34 H 4.44 N 14.23

C 68.81 H 4.69 N-15.04

C 71.28 H 4.32 N 13.85

C 72.49 H 5.17 N 12.68

C 75.15 H 7.03 N 10.11

73.00

3.79

15.84

74.09

4.71

15.05

81.29

4.41

14.22

81.19

4.57

13.92

68.99

4.63

14.92

71.31

4.44

13.85

72.38

5.42

12.36

74.87 7.16 9.94

No. Ar % The end d) G. crystallization Mp ° C h max. (27 (At the) Analysis% 76.38 found S. 0 prey G> 45.85 y ~ 37.1 solvent calculated 8.51
11.14 166 CH (CH ) CNIH-ν 154-155.5 344 240) 76.58 00 6 no.14
• 1/4 H ₂ O G· chloroform (22 C. 74.72 8.35
10.81 CO G. 29.80 - ^ 35.1 H
N 5.23 193 150-152 342 900) 14.52 74.37 H. Ethanol (27 C. 51.77 5.17 8.2 ^ - 1 / 2H ₂ O 33 _f3 H 2.72 14.33 196 178-181 330 300) N 11.32 51.89 OO Diethylformamide (21 C. 78.32 2.68 O G. water H 4.48 11.46 " co
00 219 y- 28.2 151.5-153.5 333 100) N 12.45 78.32 NJ toluene (22 C. 75.19 4.63 I.
(η OO H 4.66 12.22 Q 220 CH ₃ o - ^^ - 0 - 151.5-153.5 337 200) N 11.44 75.42 t OO
co - benzene (22 C. 72.92 4.58 01 H 4.45 11.46 221 > 300 ° 343 700) N 11.60 73.21 N— / Ethanol-water C. 4.31 (24 H 72.04
5.74 11.74 N 12.60 222 ™ 3 ^(CH 2> 3 ^S ~ Q 83-85 348 600) 71.64
5.68 I. Ethanol C.
H 12.62 K) ! N CO O CD CO CD

Ar

% The end Recrystallization Mp. ⁰ C X max. (Am) Analysis% found , 70 § prey solvent calculated , 03 UU
U) , 32 Ui IO 164-165.5 339 (19 400) 67 22.6 toluene C £ 8.05 5 H 5.11 12th N 12.53

Notes to Table VI:

a) In US Pat. No. 3,887,566, a

Called mp. 154-157 ^0C.

b) The preparation is carried out by refluxing i

equimolar amounts of 2-aminophenylimidazole and phthalic j acid anhydride in toluene for an hour and a half. After cooling, the product precipitates out of the solution.

c) Manufactured by catalytic hydrogenation with 10% Palladiunj on activated charcoal of a dimethylformamide solution of the nitro analogue; the crude product is precipitated with water.

d) Prepared by treating compound 153 with the appropriate acid chloride in pyridine and then treating Precipitation with water.

e) Produced by H J cleavage of compound No. 138.

f) Prepared by treating the lithium salt of compound no. 162 with the appropriate acid chloride in DMF and subsequent precipitation with water.

g) Prepared by treating Compound No. 151 with the appropriate nucleophile by the method of Kornblum et. al ,. J. Org. Chem. ,. 41: 1560 (1976).

h) Produced by HJ cleavage of compound 220.

80 9 8 28/0896

The 4-alkylaminoimidazo [1,2-a] -quinoxalines listed in Table VII are prepared by adding the appropriate alkylureylenes (Table III) for half an hour reacted at reflux temperature with phosphorus oxychloride and pyridine. The reaction mixture is then poured into cold water Water and removes the excess pyridine by azeotropic detillation. Dissolve the raw product in Chloroform and sends it through an alumina column. After evaporation of the chloroform, the solid becomes out crystallizes from the specified solvent and is obtained in a likewise specified yield.

809828/0896

Table VII ( Mp. ⁰ C ( -V >
r NHR 72.15
6.81
21.04 72.02
6.75
20.81 00 • 98.5-101.5 O 69.97
6.71
23.31 70.12
6.71 ·
.23.21 ω
ui
NJ yS, \ ^. NHU-MiK + fnospnoroxycnxoria 102-104 (At the) 69.00
6.24
24.76 69.14
6.35
24.60 72-74 ^ rnax. 700) I.
_ I 335 (11 480) No. 332 (11 800) 167 317 (15 K)
co
CD
CD 168 4-alkylaminoimidazo [1,2-a] -quinoxalines OO
O 169 R% 'out crystallization
prey solvent / s \ _ 4.89 hexane CH ₃ (CH ₂ J ₂ CH ₂ - 28.33 isopropyl ether Analysis%
. calculated found CH ₃ (CH ₂ ) ₂ - 7.5 isopropyl ether C.
H
N C.
H
N C.
H
N

M / 18 352 - 56 - j

The 4-arylaminoimidazo- [1,2-a] -quinoxalines listed in Table VIII are prepared by treating the appropriate arylureyls (Table IV) with an equimolar amount of phosphorus oxychloride Reacted for 1 hour in pyridine at reflux temperature. The cooled reaction mixture is then stirred in cold water, the crude solid which dissolves has separated, in chloroform, · dries and sends it through an aluminum oxide column. The chloroform is evaporated .and crystallizes the crude solid as indicated in Table VIII.

809828/0896

• ν. O OO

Tabel

VIII

Il

NH-C-NHAr

+ Phosphorus oxychloride

Ar

172 C //

CH.

4-Arylaminoimidazo [1,2-a] -quinoxalines

% Yield from crystallization solvent

7.2 ethanol-water

Mp. ⁰ C

120-123

13.1 methanol-chloroform

11.7 methanol-chloroform 153-155

13.6 methanol-chloroform 176.5-178

HAr

. (At the)

Analysis%
calculated found

CO U) K)

304 (13 800) C. 72.57 72.67 ι H 4.76 4.71 N 21.16 20.88 334 (20 700) C. 74.43 74.16 H 5.14 5.06 N 20.42 20.09 330 (20 200) C. 74.43 73.23 H 5.14 5.26 N 20.42 20.02 OO 330 (22 200) C. 65.26 65.04 ο I
J- ι ifc H 3.75 3.77 CD N 19.02 18.91
ι • 4 **
OO CD

No.

175

Ar

% Crystallization

booty solvent m.p. ⁰ C } \ max. (Am)

10.9 methanol-chloroform 178.5-180.5 344 (33,600)

Analysis% calculated found

c 58 , 38 58 15th H 3 , 06 3, 06 N 17th , 02 17, 09

CD IO OO ^. O OO CO

176

177

178

179

18.2 toluene-chloroform 193.5-195 332 (4,500)

Br

1/2

11.5 ethanol

15.0

^{10 '52} 196.5-198.5 324 (16,600)

Methanol-chloroform 184-185.5 329 (24 100)

Cl

Dimethylformamide 122-124

water

(19 600)

C 49.76
H 2.87
N 14.51

C 56.66
H 3.27
N 16.52

C 56.66
H 3.27
N 16.52

C 63.27
H 3.98
N 18.45

49.72

3.10

14.39

56.69

3.24

16.43

56.26

3.20

16.54

62.94

4.19

18.58

180

181

13.0 ethanol-dimethylformamide

9.4

Isopropanol 139

(19 810)

148.5-149.5 343 (20 230)

C 69.05
H 3.98
N 20.13

C 69.05
H 3.98
N 20.13

68.88

4.02

20.13

68.92

4.00

20.14

OO CD CD -O-CO CD

No.

182

183

184

185

186

187

188

189

Ar

OCH,

CH ₃ O

m.

% Of recrystallization

booty solvent m.p. C } \ max. (Am)

3.1 isopropanol

16.58 dimethylformamide water

11.4 dimethylformamide water

8.3 dimethylformamide water

14.12 dimethylformamide water

2.0 isopropanol

Dimethylformamide

36.4 dimethylformamide water

33.1 dimethylformamide water

139.5-141 331 (18 030)

166-168.5 347 (21 730)

207-209

366 (22 410)

116.5-117.5 335 (21 820)

147-149 339 (18 540)

195-197 341 (20 370)

241-243.5 400 (8,960)

323-324.5 368 (23 670)

Analysis%
calculated found 69.05
3.98
20.13 68.50
3.92
19.86 S. 56.66
3.27
16.52 56.31
3.25
16.56 OO awn 70.33
4.86
19.30 70.61
5.11
19.11 U)
to awn 70.33
4.86
19.30 70.16
5.28
19.31 awn awn I.
Ui
vo

C. 70.33 70.14 H 4.86 4.98 N 19.30 19.09 C. 60.28 60.21 H 3.95 3.88 N 21.97 21.63

C 62.95 H 3.63 N 22.94

C 62.95 H 3.63 N 22.94

62.62

3.63

22.68

62.73

3.73

22.81

CO O CD 4> « OO CD

No.

195

197

198

j 199

200

Ar

Q- '

• CH,

CH ₃

CH ₃ CH ₂

j 201 CH ₃ (CH ₂ )

202

% Uncrystallization yield from solvent 11.61 dimethylformamide / water

5.52 dimethylformainide - water

10.91 dimethylformainide

. 15.29 dimethylformamide water

1/4 H ₂ O 13.81 dimethylformamide

water

1/4 H ₂ O mp. ⁰ C } \ max. (Am)

138.5-141 335 (22 900)

143-145 330 (18,000)

163.5-165.5 337 (18,800)

81-83

(20 800)

124.5-127 335 (23,200)

16.96 isopropanol-water 89.5-91.5 335 (21,000)

Methanol-chloroform

187-190 342 (24 200)

Analysis% calculated

found -*

C 74.99
H 4.58
N 15.90

C 74.43
H 5.15
N 20.42

C 74.98
H 5.59
N 19.43

C 73.83
H 5.51
N 19.13

C 73.83
H 5.51
N 19.13

C 73.83
H 5.51
N 19.13

C 76.29
H 4.56
N 17.00

75.02

4.66

75.02

74.63

5.16

20.09

74.69

5.56

19.43

73.87

5.49

18.88

74.14

5.47

19.02

74.14

5.47

, 19.02

76.58

4.52

17.58

Ol tv)

OO CD CD

No.

Ar

203 CH ₃ CH ₂ O-

204 CH ₃

205 CH ₃ S - \ _ tf

206

Cl

* 1/2

• 1/4 H ₂ O

% Of ufo crystallization

booty solvent m.p. ⁰ ° C

8.5 dimethylformamide 90-97
• ·. water

max. (M)

12.50 dimethylformamide 120.5-123 340 (20 300)
water

21.39 dimethylformamide 102.5-107 340 (19,600)
water

(26 400)

; 39 dimethylformamide 129-130 347 (20 300)
water

11.49 dimethylformamide 178.5-179.5 324 (25,500)
water

7.52 dimethylformamide "172.5-173.5 345 (24,900)
water

15.18 dimethylformamide-water

170-172

(23 800)

Analysis% calculated found

C 68.99 68.32 H 5.15 5.32

N 17.88 17.61

C 62.20
H 3.38
N 17.07

C 65.68
H 4.62
N 18.02

C 62.20
H 3.38
N 17.07

C 56.29
H 2.78
N 15.45

C 65.18
H 4.18
N 17.89

61.56

3.34

17.46

65.56

4.57

17.88

61.56

3.34

17.46

55.86

2.72

15.37

C 56.29 56.13 H 2.78 2.72

N 15.45 15.35

65.35

4.15

17.91

ω cn to

CO CD CD

No.

210

211

212

213

214 CH ₃

!

Ar

Cl

(\ h- '1/2 H_0

Cl

Cl

NO _n

NO,

* 1/4 H ₂

1/4 H ₂ O

% From recrystallization yield solvent

. ° C ) \ max. (Am)

13.56 dimethylformamide- 171.5-173 337 (17,300)
water

10.78 dimethylformamide 259.5-261.5 342 (23,200)
water

19.43 dimethylformamide water

271-273

(18 400)

7.22 dimethylformamide 198-200
water

3.04 methanol-chloroform 229-231

4.18 methanol-chloroform 168-170 344 (21 400)

Analysis% S calculated found

64 , 86 64 , 92 ω 3 , 40 3 , 51 Ul C. 18th , 91 19th , 09 to H N

C 56.82 56.76 H 3.28 3.07 N 16.57 16.57

C 61.45 61.35 H 3.22 3.27 N 17.92 17.81

341 (19,900) C.
H
N 58.63
3.15
21.36 58.50
3.06
21.20 σι
NJ
ι 344 (21 400) C.
H
N 63.06
4.12
21.63 62.97
4.08
21.34 346 (19 600) C.
H
N 56.57
2.97
20.61 56.44
2.90
20.51 OO
CD
CD OO
O

OO O CD CD [> O OO

O 00 CD OO

Γ
No. N = ¹ C- j Ar % The end
prey Recrystallization
solvent • Mp. ⁰ C h max. (At the) Analysis%
calculated found S 70.48
3.91
24.17 70.89
3.94
24.09 18 352 216 (CH ₃ ) ₂ ( ι
i
j -Q- 5.96 Dimethylformamide
water 224-226.5 349 (34 700) C.
H
N 75.47
6.00
18.53
• 75, "08
6.34
18.53 218 Annotation: 2.31 Isopropanol 95-96.5 C.
H
N I. a) All Data concern the 1/4 hydrate. ω
I. • ι
\ 2800; • · * · ^
CX)
CD

Various compounds according to the invention show anti-fungic and anti-yeast effects. For example, Sa was found that they are effective against organisms such as Candida albicans (ATCC No. 10231), Candida tropicalis, Aspergillus niger (ATCC No. 16404), Trichophyton mentagrophytes (ATCC No. 8757 and 9129), Trichophyton rubrum (ATCC No. 10218 and 14001) and Trichophyton ajelloi are effective.

The anti-fungic effect of these compounds according to the invention makes them useful in dermatomycoses such as tinea capitis, Tinea favosa, Tinea barbae, Tinea corporis, Tinea imbricata, Tinea cruris, Tinea pedis, Tinea manus, Tinea unguientum and various types of candidiasis, such as glossitis, stomatitis, cheilitis, perleche, and vaginitis Balanitis.

If the compounds according to the invention are used for antifungal medical purposes, they are usually housed in a suitable pharmaceutical carrier. These anti-fungic preparations can be in the form of solutions, lotions, creams, ointments, etc. The amount of the antifungal The active ingredient varies somewhat, but is generally about 0.5 to 10.0% by weight, based on the total weight of the Preparation.

Table IX below lists the antifungal activity of a number of compounds according to the invention. This was determined by the agar dilution method as described in Chapters 2 and 3 of Methods in Microbiology, Volume 73, edited by JR Norris and DW Ribbons, Academic Press, New York, 1972.

809828/0896

M / 18 352

Tabel

IX

Antifungal activity

"Parts per Million" inhibition of fungus and yeast species

Verb. C. C. A. T. 128 100 T. T. No. albicans tropicalis niger ajelloi 100 mentagrophytes rubrum 20th 100 100 136 100 100 40 DOO 100 100 100 100 35 100 100 16 39 100 100 100 133 100 100 8th 100 8th 8th 134 100 100 16 139 100 137 100 100 135 100 100 142 100 132 100 100 138 100 100 130 100 100 100 100 113 100 100 100 9 16 16 10 16 16 116 16 16 127 16 16 109 128 32 114 16 1 118 256 4th 123 2 131 16 2 140 ^c 0, 151 1 119 8th 120 1 8th 8th 8th 16 4th 2 110 128 64 122 32 112 128 64 153 100 124 100 100 100 8th 58 100 100 59 100 62 100 100 126 100 100 145 100 100 159 100 100 160 100 100 163 100 100

809828/0896

Table IX, continued

Verb. C. C. A. T. T. T.

No. albicans tropicalis niger ajelloi mentagrophytes rubrum

164 100 100 100 165 100 100 100 167 100 100 100 168 100 100 100 169 100 100 100 173 100 100 100 179 100 100 100 182 100 184 100 100 100 185 100 100 100 186 100 100 100 189 100 100 187 100 100 123 16 129 16 16 8th

809828/0896

Some of the compounds of the invention are immunosuppressive Effect. Most of the compounds tested belonged to the 4-substituted imidazo [1,2-a] -quinoxalines of the above formula I, although also 1- (2-acylaminophenyl) imidazoles of the formula II among them are. Because of this activity they are indicated for the treatment of diseases, which according to the state of the art Technique to be treated with immunosuppressants. These include glomerulonephritis, serum sickness, organ transplants, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, chronic active hepatitis, multiple sclerosis, heterografts or homografts for burns, psoriatic arthritis, urticaria, respiratory allergies, e.g. asthma, hay fever; Scleroderma, Mycosis fungoides, dermatomyositis, psoriasis and contact dermatitis (including "poison ivy", toxicodendron radicans).

The dosage range of the immunosuppressants according to the invention depends on the particular compound being administered. He is usually that of the immunosuppressive drugs according to the state correspond to the technology. If the immunosuppressants according to the invention are administered orally or intravenously, the Daily dose usually in the range from about 0.1 mg to 15 mg per kg of body weight. If other modes of administration are used, for example depot injections, implants, etc., the dose can be considerably higher, namely up to about 100 mg / kg body weight with a single injection.

The immunosuppressive effects of the compounds according to the invention are determined by means of the hemolysin test in mice and the test for delayed hypersensitivity. The hemolysin test used is described in Methods in Immunology , edited by DH Campbell et al., WA Benjamin, New York 1963, pp. 172-175. The humoral or antibody reaction is determined. In the test

809828/0896

Delayed hypersensitivity measures the effect of a test compound on the ability of a mouse used as an experimental animal has a. Cell "mediated" ' Overcoming immune response to the antigen, Mycobacterium tuberculosis H37Ra. By subcutaneous administration in the base of the tail the mouse becomes responsible for the antigen

ι sensitized. The development of delayed hypersensitivity

The reaction can be measured at any time, starting on the 6th day after sensitization, but is usually carried out on the ninth day as follows: Purified protein derivative (tuberculin) is injected into the right hind paw, while physiological ¹ saline is injected into the left hind paw as a control . The volume of both paws is measured 24 hours later and a significant increase in the volume of the right hind paw is used as a measure of an effective, delayed hypersensitivity reaction. All compounds are administered subcutaneously.

The test results are summarized in Table X below. The designation HL (ED ₅₀ ) mg / kg ' _s . _Ci denotes the number of mg / kg body weight of subcutaneously administered drug that were necessary to reduce the antibody activity by 50% compared to the control. Thus, the lower its HL (ED ₅₀ ) value, the more effective the immunosuppressant a drug is.

The DHS (EDg ₀ ) mg / kg se. Value listed in column 3 indicates the effectiveness of a drug in reducing the edema associated with the cell-mediated immune response. It indicates the number of mg / kg body weight of drug administered subcutaneously necessary to reduce the edema of the cell-mediated immune response by 60% compared to the control. Also here it is again so, that the connection is all the more effective Immunosuppressivura, the lower the DHS (BDG ₀₎ is the value for xell-mediated immune response.

309828/0896

M / 18 352 151 - 69 - 2800480
I. DHS (ED ₆₀ ) 140 Table X ; mg / kg se. link 131 HL (ED ₅₀ ) 1.52 No. 116 mg / kg se. 1.15 117 0.3 81 118 0.26 56 109 18th 46 110 > 50 43 3 > 50 > 50 66 > 50 50 147 > 50 50 134 - > 50 137 50 1.7 135 46 7.2 142 0.027 3.2 136 0.5 0.22 133 <0.125 4.2 139 0.033 > 50 138 0.20 32 127 2.7 > 50 170 0.75 27 150 3.0 36 143 0.72 > 50 174 > 50 > 50 171 6.6 1.3 175 22nd 8.0 178 0.36 59.0 196 0.61 5.9 197 0.96 46.0 3 0.09 ¹ 45.0 169 11.0 37 146 0.42 50.0. 153 1.6 > 50.0 149 50.0 3.1 126 46 5.7 177 0.11 8.8 182 1/2 > 50.0 162 0.16 > 50.0 173 35.0 - 159 13.0 - 181 1.1 40 180 13.0 27 183 - - 158 3.0 - 157 16.0 15th 218 5.6 7.6 0.39 12th 1.0 25th 0.39 1.5

809828/0896

D.H.S. SC. mg / kg > 32 11 > 32

Continued, Table X

Compound HL (ED ₅₀ ) ^Nr · mg / kg se.

219 2.5

220 2.3

221 1.0

^ • 50 means that more than 50 mg / kg of a drug would be necessary to reduce the humoral antibody activity by 50% or to reduce the edema caused by the cell-mediated immune reaction by 60%. There these values are higher than what is of clinical interest for these compounds no further attempts made.

809828/0898

Some compounds of the invention have non-steroids anti-inflammatory effect. This seems to be the case in general in the 4-substituted imidazo [1,2-a] quinoxalines of Formula I and the 1- (2-acylaminophenyl) imidazoles of Formula II to be the case. Because of these properties, they are indicated for use in diseases in which according to the prior art, non-steroidal anti-inflammatory agents can be administered. These include ichthyosis, psoriasis, Alopecia, allergic eczema, etc.

The dosage range for the anti-inflammatory drugs of the present invention Agent may depending on the compound chosen, the disease to be treated and the mode of administration vary. When applied topically, the compounds will generally become one for topical use appropriate pharmaceutical carrier distributed. In the case of these agents, the anti-inflammatory factor according to the invention Agent about 0.5 to 15.0% by weight, based on the total weight of the agent.

The anti-inflammatory agents according to the invention can also can be administered orally, intravenously, subcutaneously, intramuscularly and intradermally. In these cases the daily dose of 0.5 to 20 mg / kg body weight of active anti-inflammatory agent according to the invention.

The anti-inflammatory activity of representative compounds according to the invention was determined using the rat paw edema test for both local administration (Table XI below) and for oral administration (Table XII). Oral administration was carried out as described by CA. Winter, EA Risley and GW «Nut, Proc. Soc. Exp. Biol. Med. TII , 544 (1962), the measurements being carried out four hours after administration of the drug.

809828/0896

The experiments with topical administration were carried out in a similar way, except that the irritant (carrageenan) was administered concurrently with the test compound at time zero.

Tables XI and XII show the anti-inflammatory Activity of the compounds tested as the percentage difference in edema or swelling compared to of control. In these tables, the response of several dosage ranges is sometimes also a single one Connection listed.

809828/0896

Table XI

Rat paw edema test, local administration (injected directly into the paw)

% Difference to control

Connection no. 1 μg 10 µg 100 µg 100 mg / kg 148 -32.6 -53.5 -14.3 -39 109 -30.8 -3.9 +31.6 114 -68.2 -30.0 -131.6 117 110 -74 122 -61 49 '. ~ ³⁵ 7th -22 51 -57 140 -78

809828/0896

M / 18

Tabel

XII

Rat paw edema test / oral administration

Connection no.

% Difference to control mg / kg 400 mg / kg

Indomethacin

Phenylbutazone

Aspirin 114 110 122 148

49 7

51 140 131 10 39 133 137 112 111 121 147 134 139 132 150 144 115 117 123 116 136 8

29 14 20 38 57 50 45 40 35 37 18 -65 -76 -57

-61 -43 -61 -52 -35 -52 -57 -35 -52 -30 -50 -17 -26 -17 -43 -61 -39 -43 -22 -76 -30 -26 + 70 -7

+ 104

-9 -22 -24 -52 -59 -41 -35 -20 -33 -43 -50 -35 -28

-68

-25

-25 -18 -50 -18 -25 -13 -25

-33

809828/0896

Table XII, continued

Connection no.

55

52

23

25th

30th

36

42

24

109

75

68

73

128

129

100 mg / kg 400 mg / kg -24 -5 -26 -26 -26 +43. -46 -30 +9 -33 - -7 -68 -9 -25 -17 -25 -17 -22 -30 -26 -22 -39 -30

809828/0896

Claims (34)

Claims (2) R is linked through a carbon-carbon bond, to a ring carbon atom and for one aliphatic, cycloaliphatic, substituted phenyl, fused bicyclic aryl group or for one substituted by monocyclic aryl aliphatic group, (3) R is hydrogen or a radical which is above a carbon-nitrogen bond to the nitrogen atom is bound, selected from aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl and monocyclic aryl substituted aliphatic groups. 8 09 828/0898 ° ^R ' ^GINAL M / 18 352 - # -% 2. Compounds according to claim 1, wherein X is -R. 3. Compounds according to claims 1 or 2, wherein -R is a saturated or unsaturated, straight-chain or branched aliphatic radical having 1 to 18 carbon atoms which can be unsubstituted or substituted by an ether or a halogen atom. 4. 4-n-Pentylimidazo [1,2-a] quinoxaline. 5. Compounds according to claim 1 or 2, wherein -R is an aliphatic group having 3 to 6 carbon atoms. 6. Compounds according to claims 1 or 2, wherein -R is substituted phenyl. 7. 4- (4-Chlorophenyl) imidazo [1,2-a] quinoxaline. 8. 4- (4-Fluorophenyl) imidazo [1,2-a] quinoxaline. 9. Compounds according to claim 1, wherein X is -NHR. 2 10. Compounds according to claim 1 or 9, wherein -R is a straight-chain alkyl group having 1 to 18 carbon atoms. 809828/0896 11. Compounds according to claim 1 or 9, wherein -R for Phenyl or substituted phenyl. 12. 4-anilinoimiadazo [1,2-a] quinoxaline. 13. 4- (4-Methylanilino) imidazo [1,2-a] quinoxaline. 14. 1- (2-Acylaminophenyl) imidazoles of the formula KHG-X ² where -X ^{2 is} -R ^S or -NHR ² ^ (1) R stands for hydrogen or an aliphatic, cycloaliphatic _r phenyl, substituted phenyl, condensed, bicyclic aryl radical or for monocyclic aryl radicals which are substituted by aliphatic groups which are bonded to the carbonyl carbon atom via a carbon bond; and (2) R stands for hydrogen or a radical which is above a carbon-nitrogen bond to the nitrogen atom is bound, selected from aliphatic, cycloaliphatic, phenyl, substituted phenyl ,, fused bicyclic aryl, and monocyclic aryl substituted aliphatic groups. 809828/0896 ". ^: ~ M / 18 352-r -H 2 5 15. Compounds according to claim 14 _f wherein -X is R. 16. Compounds according to claim 14, wherein R is a straight-chain or branched, saturated, mono-unsaturated or poly-unsaturated groups with 1 to 17 carbon atoms means, where 1 or more of the hydrogen atoms are optionally replaced by a halogen atom or a Ether can be replaced. 2 17. Compounds according to claim 14, wherein -X is -NHR stands. 18. Compounds according to claim 17, wherein -R is a aliphatic group having 1 to 18 carbon atoms. 19. Process for the preparation of 4-substituted imidazo [1,2-a] quinoxaline compounds the formula: characterized in that a 1- (2-acylaminophenyl) imidazole of the formula: 809828/0896 Reacts with so much phosphorus oxychloride that a cyclization takes place and then the 4-substituted Imidazo [1,2-aJquinoxaline wins, where -X stands for -R ⁵ or -NHR, in which: (1) R for hydrogen or an aliphatic / cycloaliphatic, Phenyl, substituted phenyl, fused bicyclic aryl radical or for through monocyclic aryl substituted aliphatic groups that have a carbon-carbon bond are attached to the carbonyl carbon atom; and (2) R ^{2 represents} hydrogen or a radical which is bonded to the nitrogen atom via a carbon-nitrogen bond, selected from aliphatic, cycloaliphatic, phenyl, substituted phenyl, condensed bicyclic aryl radicals, and aliphatic groups substituted by monocyclic aryl. 20. The method according to claim 1 9, characterized in that that R stands for a saturated or unsaturated, straight-chain or branched aliphatic radical with to 18 carbon atoms, which: unsubstituted or substituted by an ether or a halogen atom can be. 809828/0898 M / 18 352 - ^ -4r 21. The method according to claim 19, characterized in that -R ^{5 stands} for an aliphatic group having 3 to 6 carbon atoms. 22. The method according to claim 19, characterized in that -R ^{5 represents} substituted phenyl. 23. The method according to claim 19, wherein -X ^{2 is} -NHR ² , 24. The method according to claim 19 or 23, wherein -R for a straight-chain alkyl group with 1 to 18 carbon atoms. 25. The method according to claim 19 or 23, wherein R Denotes phenyl or substituted phenyl. 26. Agent for the treatment of fungal infections in mammals, characterized in that it is a therapeutic "Effective amount of at least one 4- (substituted phenyl) -imidazo [1,2-a] quinoxaline and contains a pharmaceutically acceptable carrier and / or additives. 27. Composition according to claim 26, characterized in that it contains 4-alkyl-imidazo [1,2-a] quinoxaline '. 28. Agent for the treatment of inflammatory diseases in mammals, characterized in that there is a therapeutically effective amount of a 4-alkylimidazo [1,2-a] -quinoxaline and a pharmaceutically acceptable one 8Q9828 / 0896 M / 18 352 - Contains carriers and / or additives. 29 means that the 4-Alkylimidazo [1, 2-a] quinoxaline 4-n-Pentylimidazc- the [1,2-ajchinoxalin according to claim 28, characterized. 30. Agent for weakening the immune response in mammals, characterized in that it is a therapeutic effective amount of a 4- (substituted phenyl) imidazo [1,2-a] quinoxaline and a pharmaceutically acceptable one Contains carriers and / or additives. 31. Agent according to claim 30, characterized in that the 4- (substituted phenyl) imidazo [ 1,2 -a] quinoxaline is 4- (4-chlorophenyl) imidazo [ 1,2-a] quinoxaline. 32. Agent according to claim 30, characterized in that the 4- (substituted phenyl) imidazo. [1,2-a] quinoxaline is 4- (4-pluophenyl) imidazo [1,2-a] quinoxaline. 33. Agent for weakening the immune reaction in mammals, characterized in that it contains a therapeutically effective amount of a 4- (substituted anilino) imidazo- [1,2-a] quinoxaline and a pharmaceutically acceptable carrier and / or additives. · 34. The composition of claim 33, characterized in that the 4- (substituted anilino) -imidazo [1, 2-a] quinoxaline 4- (4-methylanilino) -imidazo [1,2-a] quinoxaline. 809828/0896